The broad, long-term objective of the NIH High-End Instrumentation Award application is to acquire a new state-of-the-art high-performance small animal (SA) PET/SPECT/CT imaging system for multi-modality imaging of small animals to allow biomedical researcher at Johns Hopkins Medical Institutes (JHMI) to gain unprecedentedly clear and new information on different aspects of the anatomy, physiology, and biochemical processes involved in normal and diseased animals. The specific aims of the proposed acquisition are: (1) to replace the existing over 7-year old and outdated stand-alone small animal (SA) PET and SPECT/CT systems that are currently serving the JHMI research community, and (2) to provide users with an integrated PET/SPECT/CT system that allows accurate registration of the multimodality images. To achieve the aims, we propose to acquire a commercial Gamma Medica (GM) state-of-the-art high-performance integrated multi- modality SA PET/SPECT/CT imaging system based on a single TriumphTM gantry. The GM multimodality SA imaging system consists of four components: (1) a LabPET 12 stationary ring PET subsystem with dual-layer LYSO/LGSO scintilliators integrated with avalanche photodiode (APD) detectors and with 12 cm axial field-of- view, (2) a SPECT subsystem with 2 -head state-of-the-art solid-state cadmium zinc telluride (CZT) detector based camera modules with high-energy resolution that is especially important for multi-isotope imaging, (3) a high-resolution microCT subsystem with tunable x-ray generator and variable micro focal-spot x-ray tube with highest achievable resolution of less than 35 micron and the special pulsed x-ray tube also allow respiratory gated CT studies, and (4) state-of-the-art SA imaging accessories including a physiological monitoring system that simultaneously monitors temperature, ECG and respiration, a anesthesia system, an injection pump, a blood counter and exfusion pump for input function measurements for small animals. The proposed multi- modality SA PET/SPECT/CT system will be housed in the existing Small Animal Imaging Center (SAIC), together with a 9.4T small bore MRI system, a Xenogen IVIS 200 optical imaging system, and a Visual Sonics SA ultrasound imaging system. This combination represents the most complete and state-of-the-art multimodality SA imaging facility. The operation of the proposed equipment will be overseen by an Advisory Committee formed by the PI, the Co-PI and the major users across JHMI. The Advisory Committee will meet twice a year to review the operation of the SA imaging suite and to set policies and procedures to assure equitable use of the proposed equipment.